Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide

Abstract

In this part of a series on founder mutations in the Netherlands, we review a Dutch family carrying the SCN5a 1795insD mutation. We describe the advances in our understanding of the premature sudden cardiac deaths that have accompanied this family in the past centuries. The mutation carriers show a unique overlap of long-QT syndrome (type 3), Brugada syndrome and progressive cardiac conduction defects attributed to a single mutation in the cardiac sodium channel gene SCN5a. It is at present one of the largest and best-described families worldwide and we have learned immensely from the mouse strains with the murine homologue of the SCN5a 1795insD mutation (SCN5a 1798insD). From the studies currently performed we are about to obtain new insights into the phenotypic variability in this monogenic arrhythmia syndrome, and this might also be relevant for other arrhythmia syndromes and the general population. (Neth Heart J 2009;17:422-8.).

Keywords: Brugada syndrome; cardiac sodium channel disease; conduction disease; long-QT syndrome; sudden cardiac death.

Figure 1

ECGs of the first family member identified throughout the past 50 years. Note the severe repolarisation abnormalities indicative of long-QT syndrome type 3 already apparent in the first ECG (A). During those 50 years the PQ and QRS interval clearly prolong, indicative of progressive cardiac conduction defects in both atria and ventricles (B and C).

Figure 2

ECGs of three different family members carrying the SCN5a 1795insD mutation where the huge phenotypic variability and overlap syndrome can be clearly appreciated. The presence of this overlap syndrome brought us to recognise several mutation carriers who were not earlier linked to the family. ECG A shows predominantly a long-QT syndrome type 3 phenotype with excessive QT prolongation during bradycardia. ECG B shows predominantly a Brugada syndrome phenotype with elevated coved-type ST segments, low initial R waves in the right precordial leads, broad P waves and QRS complexes, but also QT prolongation. ECG C shows a milder mixed phenotype with a first-degree AV block, wide QRS complexes, a coved-type like ST-segment in V1 and QT prolongation.

Figure 3

Distribution of the family in the Netherlands. The founder effect can be appreciated with highest prevalence in the north (Friesland, Groningen).

Figure 4

Scatterplots showing the overlap between mutation carriers (filled boxes) and non-carriers (open circles) for (A) PQ interval vs. QRS duration, (B) J elevation vs. QTc interval and (C) QTc interval vs. RR interval. Lines represent upper limits of normal values. It can be appreciated that mutation carriers show the worst phenotypes and that there is a positive relation between PQ and QRS prolongation and J elevation and QTc prolongation. Additionally the bradycardia dependent QTc prolongation can be appreciated.

Figure 5

Kaplan-Meier plot showing survival (mortality) with or without antibrady-pacing in mutation carriers vs. non-carriers. It can be appreciated that there is a clear benefit from antibrady-pacing. However, also in the group with antibrady-pacing, mortality is observed from the age of 45 years. The three deaths between 45 and 55 years of age in this latter group were siblings.